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2007-05-08-11 Antiphospholipid syndrome and pregnancy © Dudarewicz www.thefetus.net/
Antiphospholipid syndrome and pregnancy

Lech Dudarewicz, MD, Lucjusz Jakubowski, MD, PhD.

Address correspondence to: Lech Dudarewicz, M.D., Polish Mother’s Memorial Hospital, Department of Genetics, 281/289 Rzgowska St. 93-338 Lodz, Poland; Ph: 48 42 271 11 83.

Synonyms

Antiphospholipid syndrome, APS, lupus erythematosus, lupus,  LE, lupus anticoagulant, systemic lupus erythematosus, SLE.

Definition

Presence of pathological hypercoagulability associated with the occurrence of lupus anticoagulant (LAC) and/or antiphospholipid [aPL; mainly anticardiolipin (aCL)] antibodies.

Diagnosis

The occurrence of one clinical criterion with one biological criterion defines the syndrome.

Clinical criteria

Clinical criterion is each of the following:

  • Fetal loss: the strict criterion should be 3 or more spontaneous abortions with no more than one live birth or unexplained second or third trimester fetal death.

  • Thrombosis: unexplained venous or arterial thrombosis including transient ischemic attacks or amaurosis fugax.

  • Autoimmune disorder: thrombocytopenia of less than 100,000 cells/mm3, after exclusion of other causes of thrombocytopenia, unexplained positive result from the Coombs test, hemolytic anemia with reticulocytosis, after exclusion of other causes, leukopenia of less than 4000 cells/mm3, lymphopenia of less than 1500 cells/mm3.

  • Neurologic disorder: chorea/chorea gravidarum. Criteria include seizures in the absence of other causes or psychosis in the absence of other causes.

  • Cutaneous manifestations: peripheral ischaemia including cyanosis, ulcers, after exclusion of other causes, discoid rash, photosensitivity.

  • Arthritis, serositis, in the absence of other causes.

  • Renal disorder: proteinuria of 0.5 g/d or the presence of cellular casts, without another cause, is a criterion for APS.

Biological criteria

Biological criterion is each of the following:

  • Positive ELISA test for the following antibodies:
    Antiphospholipid, Anticardiolipin, Antiphosphatidylinositol, Antiphosphatidylserine, Antiphosphatidylcholine, Anti–beta-2 glycoprotein I, Antinuclear antibody, Anti-DNA Anti-Sjögren syndrome

  • Positive coagulation test for lupus anticoagulant

Prevalence

Antiphospholipid antibodies occur in less than 2-4% of healthy individuals and up to 20% of recurrent pregnancy loss/infertility patients. They are more prevalent in women than men.

Etiology

Hypercoagulability associated with the presence of antiphospholipid antibodies, however the presence of the antibodies alone in the absence of other clinical symptoms does not define the syndrome. Hypercoagulability associated with pregnancy increases the risk of complication, thus pregnancy complications often are the first sign of the disease.

Pathogenesis

aPL antibodies increase the probability of thrombus formation by the following mechanisms:

  • damage to the endothelial cells, shifting the balance between the production of  prostaglandin E2 and thromboxane

  • reactivity with platelet phospholipids, favoring platelet aggregation

  • interference with complement activation

In addition there is a likelihood of a direct interaction of aPL antibodies with placental structures, namely with trophoblast syncytium phosphatidylserine. In animals immunized with aCL there is increased incidenc of fetal loss and thrombocytopenia, correllating with the levels of aPL antibodies. Also the administration of different aPL antibodies from humans with APS or autoimmune mice into naive mice has been shown to induce growth retardation and fetal loss.

Pregnancy complications

Fetal loss, spontaneous abortion, recurrent spontaneous abortions, pregnancy-induced hypertension, preterm delivery, uteroplacental insufficiency, glomerulonephritis, encephalopathy, seizures, ischemic stroke, thrombocytopenia, hemolytic anemia, leukopenia , subarachnoid hemorrhage.

Associated anomalies

Very interesting is the hypothesis of Carolyn B Coulam, linking the presence of aPL antibodies to congenital anomalies resulting from the vascular accidents attributable to thrombus formation. The spectrum of these defects comprises oromandibular hypogenesis and kidney defects. There are however too few observations to draw firm conclusions.

Differential diagnosis

Other causes of recurrent spontaneous pregnancy loss, including: other causes of hypercoagulability: thrombofilic mutations, antithrombin III deficiency and protein C deficiency, other causes of thrombocytopenia, parental chromosomal abnormalities, intrauterine infections, anatomic defects of the uterus (congenital and acquired e.g. Asherman syndrome), endocrine disorders, luteal-phase deficiency, thymic tumors, HIV infection.

Prognosis

Good, if fractionated heparin and aspirin treatment is started before the pregnancy. Of note is the fact, that untreated women with the diagnosis of antiphospholipid syndrome have approximately 90% risk of fetal loss.

Recurrence risk

Increased risk of hypercoagulation-related complications for future pregnancies. Unknown, but perhaps also increased risk of developing antiphospholipid syndrome for the offspring of affected patients.

Management

Anticoagulation, antiaggregation therapy.

Warning

Women with antiphospholipid syndrome should not take estrogen-progestin combination oral contraceptives.

Case report

A 26-year-old G3P3 woman had a past medical history significant for emergency cesarean delivery in the 27th week of her second pregnancy, complicated by imminent intrauterine asphyxia caused by placental insufficiency. The child died soon after delivery due to hypoxia and prematurity. She was subsequently found positive for anticardiolipin antibodies.

From the beginning of her third pregnancy she was placed on fractionated heparin (Clexane). Until 19 weeks, the course of the pregnancy was uneventful. In the 19th week the size of the fetus was discrepant with the menstrual age and with the ultrasound dating from the first trimester. The head was two weeks smaller, than expected, and the abdominal circumference, femur length and humerus length were almost four weeks smaller than expected. The amniotic fluid volume was reduced (AFI=6.5 cm). There was cardiomegaly and some thickening of the myocardium of both ventricles of the heart. Echogenic intracardiac focus was present in the left ventricle. The anatomy of the heart was otherwise normal: normal outflow tracts and three-vessel view. There was absent diastolic flow in the umbilical arteries and pulsatility was present in the umbilical vein. There was reversed A wave in the ductus venosus. The placenta was thickened, approximately up to 3.7 cm and of markedly inhomogeneous echogenicity. The bowel of the baby was admittedly no more echogenic, than the iliac bones, but subjectively judged as of increased echogenicity, even at low ultrasound frequency.

The patient was negative for TORCH infections. The fetal karyotype was 46, XY.

At 26 weeks the fetus died in utero. After birth no structural anomalies were noted. The baby weighted 230 grams, which is below 3rd centile for 26 weeks.

Figures 1, 2: Thickened and inhomogeneous placenta.

 

Figures 3, 4: Hyperechogenic bowel.

 

Figures 5, 6: Figure 5 - pulsed Doppler sonogram shows absent end-diastolic flow in the umbilical arteries, and pulsatile flow in the umbilical vein. Figure 6 - pulsed Doppler sonogram shows reversed A wave in the ductus venosus.

 

Figure 7, 8: Image 7 - slight cardiomegaly with a small pericardial effusion. Image 8 - abdominal circumference equivalent to 15+4 weeks at 19 weeks of gestational age.

  

Conclusions

The diagnosis of APS requires co-existence of clinical and laboratory findings. As far as the reproductive process is concerned, in most patients either there is a fetal loss attributable to abnormal placental function, or there is a normal course of pregnancy. Our patient is distinctive, because of the fact of discovering very early symptoms of placental failure, in spite of anticoagulant therapy.
Besides fetal loss, APS patients are at risk of venous thrombosis, even up to the catastrophic embolus. One of the safety measures is color flow Doppler examination of the IVC which is safe and inexpensive. The signs and symptoms of thrombosis particularly in puerperal APS patients have very low reliability. In the APS patients a high index of suspicion for venous thrombosis should be maintained.

References

- Aoki K, Matsuura E, Sasa H, Yagami Y, Dudkiewicz AB, Gleicher N. beta 2-Glycoprotein I-dependent and -independent anticardiolipin antibodies in healthy pregnant women. Hum Reprod. 9(10):1849-51; 1994
- Coulam CB. Hypothesis: antiphospholipid antibodies associated with congenital anomalies? Early Pregnancy. 3(2):109-12; 1997

 

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